University of Illinois Urbana-Champaign

Studies towards the synthesis of bielschowskysin and total synthesis of darobactin A

Nesic, Marko

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NESIC-DISSERTATION-2023.pdf

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https://hdl.handle.net/2142/120220

Description

Title
Studies towards the synthesis of bielschowskysin and total synthesis of darobactin A
Author(s)
Nesic, Marko
Issue Date
2023-04-03
Director of Research (if dissertation) or Advisor (if thesis)
Sarlah, David
Doctoral Committee Chair(s)
Sarlah, David
Committee Member(s)
  • Denmark, Scott E.
  • Silverman, Scott K.
  • Mitchell, Douglas A.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
  • bielschowskysin
  • darobactin
  • total synthesis
  • Larock indole synthesis
  • macrocycle
  • macrocyclization
Abstract
The isolation of evermore complex natural products has been continuously inspiring chemists to achieve total syntheses of such targets, while pushing the frontiers of the field of organic synthesis. The intellectual challenges encountered in these endeavors have tested the limits of our current knowledge and resulted in development of novel methodologies, thereby providing significant advancements in the field. Moreover, total synthesis of natural products that have promising bioactivity has had great merit in identifying novel pharmacophores and leads, thereby directly impacting the field of medicinal chemistry. The first chapter of the dissertation describes our approach towards the total synthesis of beilschowskysin, a marine furanocembranoid diterpenoid with impressive antimalarial and cytotoxic activity. The daunting structure of this natural product has posed a great challenge for the synthetic community, making it one of the most intractable natural products ever discovered. While most of the past approaches towards this molecule relied on a [2+2] cycloaddition to form the strained core, our study was based on a different paradigm, accessing this unprecedented molecular framework via a Norrish-Yang photocyclization. Herein, we describe our successful synthesis of the macrocyclic precursor for the aforementioned photocyclization and further investigation of this key step. The second chapter will focus on our total synthesis of darobactin A, a bismacrocyclic heptapeptide, that was recently isolated from a bacterial symbiont of entomopathogenic nematodes. This natural product has shown remarkable antibacterial activity, selectively targeting gram-negative pathogens via a novel mechanism of action. We have developed a concise and convergent synthesis of this antibiotic, via sequential halogen-selective Larock indole syntheses.
Graduation Semester
2023-05
Type of Resource
Thesis
Handle URL
https://hdl.handle.net/2142/120220
Copyright and License Information
Copyright 2023 Marko Nesic

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